Role of the renal organic anion transporter OAT1 in metabolism and physiology

肾脏有机阴离子转运蛋白 OAT1 在代谢和生理学中的作用

• 批准号: 10408067
• 负责人: SANJAY K NIGAM
• 金额: $ 46.72万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10408067
• 关键词: 3-Dimensional; ATP-Binding Cassette Transporters; Antibiotic Therapy; Antibiotics; Antioxidants; Attention; Binding; Biochemical Pathway; Biological Assay; Body Fluids; Branched-Chain Amino Acids; CCL21 gene; Collection; Computational Biology; Data; Diabetes Mellitus; Diet; Diet Modification; Disease; Disease model; Docking; Drug Transport; Ensure; FDA approved; Fatty Acids; Fatty acid glycerol esters; Functional disorder; Future; Gene Expression; Guidelines; High Fat Diet; Human; In Vitro; Insulin Resistance; Interferometry; Intestines; Kidney; Knock-out; Knockout Mice; Label; Ligands; Liver; Mediating; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolic syndrome; Metabolism; Metabolite Interaction; Methods; Modeling; Mus; Network-based; Obesity; Organic Anion Transporters; Organoids; Pathologic; Pathway Analysis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Physiological; Physiology; Play; Publishing; Radiolabeled; Regulation; Research Personnel; Role; Signaling Molecule; Students; Substrate Specificity; Techniques; Testing; Time; Tissues; Validation; Vitamins; base; design; dietary; genome-wide; gut microbiome; in silico; in vivo; induced pluripotent stem cell; knockout animal; metabolomics; novel therapeutics; reconstruction; success; transcriptomics; uptake

PROJECT SUMMARY/ABSTRACT Owing to new regulatory guidelines, the organic anion transporter (OAT1)--a transporter discovered by the PI's group (as NKT) and which is involved in the elimination of many common drugs--has received considerable attention. But nearly all the published studies continue to focus on common drugs rather than endogenous substrates of the transporter, which is highly conserved from an evolutionary standpoint. Metabolomics analysis of our Oat1 knockout mice (Oat1KO), as well as in vitro transport data, indicate that OAT1 is a major transporter of metabolites, signaling molecules, vitamins, gut microbiome products, and antioxidants. Our previous genome-scale metabolic reconstructions of altered metabolism of the Oat1KO mouse under normal dietary conditions enabled us to create the first multispecific "drug" transporter (OAT1)- centered metabolic network--which was further supported by considerable metabolomics and in vitro data. Many pathways (e.g., fatty acids, gut microbiome products, branched chain amino acids) in this largely validated network of ~150-200 metabolites are also known to be important in metabolic diseases such as diabetes, metabolic syndrome, obesity, and gut microbiome-associated illness. In this proposal: 1) We will use dietary modifications (e.g., high fat, branched chain amino acids) and antibiotic treatment of the Oat1 KO mice to define the role of Oat1 under conditions applicable to metabolic diseases. We will test the binding of metabolites revealed by metabolomics under the various dietary conditions (or disease models) using a high throughput unlabeled (BLI) assay to quantify the interaction of metabolites with OAT1; this information will be used to prioritize metabolites for subsequent uptake assays involving the use of radiolabeled compounds. 2) We will then use this information, together with gene expression data from the knockout tissues under various dietary conditions, to reconstruct a metabolic network for each of these dietary (pathological model) conditions- -using methods we have previously successfully used to create an "OAT1-centered metabolic network" under normal dietary conditions. Together, these studies will help define the unique roles of OAT1 in regulation of aberrant metabolism in these dysregulated metabolic states. Finally, we discuss how this information will set the stage for understanding aspects of drug-induced metabolic syndrome in patients taking OAT1- transported drugs. We have proven expertise in the necessary techniques and a team of world-class collaborators to ensure success.

项目总结/摘要 由于新的监管指南，有机阴离子转运蛋白（OAT 1）--PI发现的转运蛋白 集团（如NKT），并参与消除许多常见药物-已收到相当大的 关注但几乎所有已发表的研究都继续关注普通药物，而不是内源性药物 转运蛋白的底物，从进化的角度来看高度保守。代谢组 对我们的Oat 1敲除小鼠（Oat 1 KO）的分析以及体外转运数据表明，OAT 1是一种 代谢物、信号分子、维生素、肠道微生物组产物的主要转运蛋白，以及 抗氧化剂我们之前对Oat 1 KO代谢改变的基因组规模代谢重建 正常饮食条件下的小鼠使我们能够创建第一个多特异性“药物”转运蛋白（OAT 1）- 中心的代谢网络-这是进一步支持了相当多的代谢组学和体外数据。 许多途径（例如，脂肪酸，肠道微生物组产物，支链氨基酸）在这很大程度上 还已知约150-200种代谢物的经验证的网络在代谢疾病中是重要的， 糖尿病、代谢综合征、肥胖和肠道微生物组相关疾病。在本建议中：1）我们将使用 饮食改变（例如，高脂肪、支链氨基酸）和抗生素治疗的Oat 1 KO小鼠 确定燕麦1在适用于代谢疾病的条件下的作用。我们将测试 代谢组学揭示的代谢物在各种饮食条件下（或疾病模型），使用高 通量未标记（BLI）试验，以定量代谢物与OAT 1的相互作用;该信息将 用于对代谢物进行优先级排序，以用于随后的摄取测定，包括使用放射性标记的化合物。（二） 然后，我们将使用这些信息，以及在各种条件下敲除组织的基因表达数据， 饮食条件，以重建这些饮食（病理模型）条件中的每一个的代谢网络- - 使用我们以前成功用于创建“OAT 1为中心的代谢网络”的方法， 正常的饮食条件。总之，这些研究将有助于确定OAT 1在调控中的独特作用。 在这些失调的代谢状态下的异常代谢。最后，我们将讨论这些信息将如何 为了解服用OAT 1的患者中药物诱导的代谢综合征的各个方面奠定基础- 运输毒品。我们在必要的技术和世界一流的团队方面拥有成熟的专业知识， 合作伙伴，以确保成功。